Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis
- University of Bonn, Germany
- Universitätsklinikum Erlangen, Germany
- German Center for Neurodegenerative Diseases, Germany
Abstract
During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.
Data availability
RNA-seq data from bulk and single-cell experiments are available under GEO accession number GSE225444. Source data for CODEX pictures (raw .tiff files) and analyses are available as pyramidal file at Dryad (Mass, Elvira (2023), Source Data Kayvanjoo et al., Dryad, Dataset, https://doi.org/10.5061/dryad.fn2z34v00). Due to size restrictions, the original CODEX .czi files could not be uploaded, but will be made available without restrictions after contacting the corresponding author.
-
Source Data Kayvanjoo et al. CODEX of fetal livers at E14.5Dryad Digital Repository, doi:10.5061/dryad.fn2z34v00.
Article and author information
Author details
Amir Hossein Kayvanjoo
Funding
Deutsche Forschungsgemeinschaft (EXC2151-390873048)
- Joachim L Schultze
- Eva Kiermaier
- Marc Beyer
- Andreas Schlitzer
- Elvira Mass
Deutsche Forschungsgemeinschaft (505539112)
- Stefan Uderhardt
Hightech Agenda Bavaria
- Stefan Uderhardt
Horizon 2020 Framework Programme (101039438)
- Stefan Uderhardt
Deutsche Forschungsgemeinschaft (GRK2168)
- Katharina Mauel
- Elvira Mass
Deutsche Forschungsgemeinschaft (GRK1873/2)
- Elvira Mass
Deutsche Forschungsgemeinschaft (SFB1454)
- Joachim L Schultze
- Marc Beyer
- Andreas Schlitzer
- Elvira Mass
Deutsche Forschungsgemeinschaft (FOR5547 - Project-ID 503306912)
- Elvira Mass
Boehringer Ingelheim Stiftung
- Katharina Mauel
Horizon 2020 Framework Programme (851257)
- Elvira Mass
Deutsche Forschungsgemeinschaft (448121430)
- Stefan Uderhardt
Deutsche Forschungsgemeinschaft (405969122)
- Stefan Uderhardt
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations of the LANUV and Veterinary Office of the City of Bonn. All of the animals were handled according to approved institutional animal care at the LIMES GRC. The protocol was approved by the LANUV (Permit Number: 2018.A056).
Copyright
© 2024, Kayvanjoo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,178
- views
-
- 315
- downloads
-
- 10
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis
eLife 13:e86493.
https://doi.org/10.7554/eLife.86493
Further reading
-
- Developmental Biology
- Neuroscience
We established a volumetric trans-scale imaging system with an ultra-large field-of-view (FOV) that enables simultaneous observation of millions of cellular dynamics in centimeter-wide three-dimensional (3D) tissues and embryos. Using a custom-made giant lens system with a magnification of ×2 and a numerical aperture (NA) of 0.25, and a CMOS camera with more than 100 megapixels, we built a trans-scale scope AMATERAS-2, and realized fluorescence imaging with a transverse spatial resolution of approximately 1.1 µm across an FOV of approximately 1.5×1.0 cm2. The 3D resolving capability was realized through a combination of optical and computational sectioning techniques tailored for our low-power imaging system. We applied the imaging technique to 1.2 cm-wide section of mouse brain, and successfully observed various regions of the brain with sub-cellular resolution in a single FOV. We also performed time-lapse imaging of a 1-cm-wide vascular network during quail embryo development for over 24 hr, visualizing the movement of over 4.0×105 vascular endothelial cells and quantitatively analyzing their dynamics. Our results demonstrate the potential of this technique in accelerating production of comprehensive reference maps of all cells in organisms and tissues, which contributes to understanding developmental processes, brain functions, and pathogenesis of disease, as well as high-throughput quality check of tissues used for transplantation medicine.
-
- Developmental Biology
- Genetics and Genomics
Smads and their transcription factor partners mediate the transcriptional responses of target cells to secreted ligands of the transforming growth factor-β (TGF-β) family, including those of the conserved bone morphogenetic protein (BMP) family, yet only a small number of direct target genes have been well characterized. In C. elegans, the BMP2/4 ortholog DBL-1 regulates multiple biological functions, including body size, via a canonical receptor-Smad signaling cascade. Here, we identify functional binding sites for SMA-3/Smad and its transcriptional partner SMA-9/Schnurri based on ChIP-seq peaks (identified by modEncode) and expression differences of nearby genes identified from RNA-seq analysis of corresponding mutants. We found that SMA-3 and SMA-9 have both overlapping and unique target genes. At a genome-wide scale, SMA-3/Smad acts as a transcriptional activator, whereas SMA-9/Schnurri direct targets include both activated and repressed genes. Mutations in sma-9 partially suppress the small body size phenotype of sma-3, suggesting some level of antagonism between these factors and challenging the prevailing model for Schnurri function. Functional analysis of target genes revealed a novel role in body size for genes involved in one-carbon metabolism and in the endoplasmic reticulum (ER) secretory pathway, including the disulfide reductase dpy-11. Our findings indicate that Smads and SMA-9/Schnurri have previously unappreciated complex genetic and genomic regulatory interactions that in turn regulate the secretion of extracellular components like collagen into the cuticle to mediate body size regulation.
